SEVENTH MEETING

James L. McGaugh, Ph.D.
Director, Center for the Neurobiology of Learning and Memory
University of California-Irvine

CHAIRMAN KASS: Let me just remind Council
members that we are in the midst of a three month inquiry into various
uses of biomedical technology, present and projected, for purposes that
go beyond the treatment of individuals with known diseases and
disorders or that have uses that could go beyond those purposes, and we
are doing so because we were, by executive order, encouraged to
undertake some fundamental inquiry into the human and ethical
significance of developments in biomedical technology and to contribute
to the public understanding of these questions.

And that meant at least that we have the
opportunity, but also the liberty to step back from some hot button
topics and to try to take a look at the field as a whole and to
discover whether there are certain kinds of questions that cut across
the uses of this or that technology.

And as I suggested in the memo that was
circulated to you before, the prospect of these kinds of uses of
biomedical technology really do raise for us some of the weightiest
questions in bioethics, as we saw this morning, already touching on not
just the means that are to be used, but also the ends that we wish to
pursue and touching very often on certain fundamental features of human
life.

We've been looking at technologies that
affect the body, whether in terms of muscle enhancement or blood doping
for athletics. We will be talking in December about research on aging
and the human life span, and we have been looking now -- this will be
the second of three sessions in which we will be looking at
technologies that offer the possibility of influencing certain features
of the human psyche, mood and affect the last time; next time,
attention and conduct and the discussions of Ritalin and the use of
stimulants; and this time things that affect memory and cognition.

And we are very, very fortunate to have with us
today two of the leading researchers in the field of human memory. Dr.
James McGaugh, since the 1950s, has been a pioneer in the neurobiology
of learning and memory. He's Professor in the Departments of
Neurology and Behavioral Science, Psychiatry, Pharmacology, the School
of Social Sciences, and the Director of the Center for Neurobiology of
Learning and Memory at the University of California at Irvine.

And we have PROF. Daniel Schacter, who has
written very widely and for a broad, nonspecialist audience wonderful
books on the psychology of memory. He's the William R. Keenan
PROF. and Chair of the Department of Psychology at Harvard.

We're delighted to have both of you with
us, and by prior arrangement Dr. McGaugh will go first. We'll then
take our break after about an hour and a half, and then we'll have
PROF. Schacter's presentation.

But the conversation can flow with all of you
present. Please, Dr. McGaugh, thank you for being with us.

DR. MCGAUGH: Well, thank you very much for
inviting me. It's nice to come here and speak about a topic that I
have been interested in for over four decades and which serves as my
current interest, deep current interest, at the present time.

I'm going to talk about memory, and I think
we can all agree that memory is a good thing to have. You'll hear
later on this afternoon that it comes in different forms and provides
different advantages and different disadvantages.

But I'm going to focus on only one aspect
of it, and that is the experimental or other treatments that will make
long lasting memories longer lasting and stronger, and the general
assumption underlying this, which certainly can be questioned, is that
if it's good for us to have memories that enable us to get along
during the day, to remember where we parked our car, to remember our
motor skills, and so on, then maybe it's a good idea to have a
little bit more of that. That's an underlying assumption
that's been made. I'm even going to question that assumption.

Now, there are several reasons for
investigating memory enhancement which I'll start with later.
I'll talk about memory blocking and start with memory enhancement.

First is just the basic research on brain
memory, and that's what drives my research. I use drugs and other
treatments to enhance memory in order to understand how the brain
ordinarily works when memories are made. That's the purpose of it.

If we take drugs, in particular, if we know
something about the mechanism of actions of drugs, let's suppose we
give a drug which is a GABA receptor antagonist, and we find that this
drug does something to memory in a very precise way. Then we can
conclude that GABA receptors located in some places of the brain are
very important in the making of the memory process.

Beyond that, if we focus on those places in the
brain, we can learn much more about not only the receptors of a
particular kind, but a receptor in a particular location.

And out of this is unraveling little by little
more and more understanding of the key neurochemical systems and the
key anatomical systems that are involved in making and preserving
memory. So that's a fundamental line of inquiry that drives this
research, where memory enhancement is a way of inducing the brain to
behave in a different way so that you can learn something about it.

Another more obvious reason is the question for
finding treatments for memory disorders, such as Alzheimer's
disease. I probably shouldn't say "such as Alzheimer's
disease" because the research is almost restricted to that.

There isn't any research on the drug
effects for the mentally retarded or it's just minuscule research.
There isn't any research for drug effects on people who have brain
damage that prevent them from learning and remembering. That's a
nascent field. It really doesn't exist.

The focus has been on progressive disorders of
learning and memory and cognition that are progressive, such as
Alzheimer's disease, because as you know, the incidence is
estimated to be at least 25 percent, if not 30 percent, in people over
the age of 85.

So we're all looking at something that can
happen to us. So it drives our attention.

Now, there are other interests of the
pharmaceutical companies and the biotech companies that overlap, but
differ somewhat from the two categories that I've given you, and
one is looking for treatments for a new disease, which is age related
memory decline.

Now, that's a new disease because drugs can
be found to treat it. It was new to me that it was a disease. I
thought normal aging was normal aging, and we have known for at least a
couple of decades that there is, on average, a slow decline over the
decades starting at the age of 30 in cognitive processing on memory
tasks, in particular, memory tasks that use speed as a criterion.

For example, if you ever watch
"Jeopardy," you don't see many 80 year old people on
"Jeopardy" because of speed of response is such a high
priority, but those of us who are over 50 or well over 50 know that we
curse the television because we know, but we can't respond as
quickly as the folks that are there.

I'm also concerned about that because while
there is age related memory decline, without question, on average there
are plenty of people who show absolutely no age related memory decline,
and there are others who show rapid age related memory decline.

And underlying all of that, by the way, is a
countervailing influence which is an increase in knowledge and wisdom
and ability to deal with the environment, which readily compensates for
the speed driven responses. But that is a new target for drug
development.

Another target for drug development which
sometimes is said explicitly, but most of the time it's implicitly,
is just drug improvement for everybody else, and why not? And why not?

If you look at the health stores or even your
drugstores or your supermarkets, you can find dozens, if not hundreds,
of bottles and packages on the shelf which are entitled something like
"memory boosters" or "brain busters" or something
of that kind, and they're not on the shelves because people want to
fill up the shelves and make them look pretty. They're on the
shelves because they're being sold.

Ginkgo biloba, which is now the latest study
shows has no effect at all in age related memory decline, still sells,
makes millions and millions of euros in Germany and, I suppose,
somewhat less than that here, but nonetheless, I get more questions
about ginkgo biloba than anything else appearing on my E-mail screen.

But that's a target you can see. That is,
as soon as you see there is a market, you can see that there's a
target for it, and so there is a slippery slide from disorders of
memory to the new disease of age related memory decline, which is in
normals, to just having a drug to improve memory in normal subjects.

Now, I have done a nonscientific sample of this
by just asking lots of people I know. I've asked if there were a
drug that was safe and effective and would improve your memory for such
things as where I parked my car yesterday or, you know, things of that
kind. I have yet to find anyone who said, "No, I wouldn't be
interested in it."

And I would have thought that most people would
say, "No, you'd have to convince me to take it." But
even people whose judgment I trust and have trusted and maybe no longer
trust have said, yes, they would take it.

And then I had another question. I said,
"Well, let's ask how eager you are. Would you do it if it was
free? How about a penny a day? How about ten dollars a day? How
about a hundred dollars a day?"

Well, they drop off, of course. Now, the
drop-off doesn't occur for family members of people who have memory
disorders. The drop-off is not really quite so steep because they will
do anything to try to keep their family members more cognitively
competent for a longer period of time.

But what this nonscientific study tells me is
that this is almost a frivolous kind of thing for most people. Yes, if
we're there, and, yes, if it were cheap, and if it would give me a
slight edge, yes, I would do it.

And don't misunderstand. The
pharmaceutical companies and biotech companies are listening to that by
looking at the sales of ginkgo biloba and other ones.

ow, there are other reasons you have to come
that are implicit, unstated. One of them is memory enhancement in
children, that is, school children, just regular school children.
I'm not talking about children with disorders.

I was driving to a concert with a neighbor, and
our families went, and she said, "Oh, Jim, I'd like to have a
drug for my daughter to make her more competitive in school. Could you
give me the name of one?"

It wasn't "do you know anything about
it," "are there any things that are safe and
effective." It was "can you give me the name of one,"
and the model that she had in mind was Ritalin because some of her
children friends take Ritalin. So there must be something else that
her child could take so that she wouldn't have to study very hard,
you know, just to make up the difference.

But I think that that's coming down the
road, and it's something I think appropriate for this group because
that's part of the slippery slope. If there is a drug which is
safe and effective and not too expensive for enhancing memory in normal
adults, why not normal children? After all, they're going to
school, and what's more important than education of the young? And
what would be more important then than to give them a little chemical
edge in getting a better education if it didn't do damage, and so
on?

So I see that that's there.

Now, we also have genetic manipulation, which
I'll talk about perhaps a little bit more later down the line.
Many of you, I'm sure, saw the cover of Time magazine and read the
article after the report of a genetic manipulation which increased the
number of a certain kind of receptors, glutamate receptors in the
brain, and the mice that had that genetic manipulation, those mice were
better at a couple of memory tasks than were other mice.

And so all of a sudden Time magazine began
talking about designer babies, I think, which would fit in with your
topic of discussion this morning. If you think selecting for sex is a
problem, think about selecting for learning or selecting for
intelligence using genetic manipulation, gene transfer or knockouts or
something of that kind. I think that is an incredible morass.

Now, as we consider these latter, however, in
children and even for adults, there's an important confusion to
clear up that was not cleared up by Time magazine, on the contrary, and
that is the distinction between intelligence and memory.

All these things do -- all of these things do,
including all of the drugs that I work with, is make animals and humans
remember a little better information that they have been presented.
That's all they do.

Now, intelligence is quite another matter,
whether you think of it conceptually or whether you think of it the way
it's tested in an intelligence test. Memory is a very small
component and memory tests are small components of intelligence tests.
They have to do with reasoning. They have to do with judgment. They
have to do with all kind of things, and there's no evidence that
inserting a gene or taking a gene away from a mouse imparts it with
greater ability to make better judgment, better reasoning or anything
of that kind.

So I think that these experiments, however
interesting, do not lead to the conclusions that were jumped on by Time
magazine, that all of a sudden we can do genetic engineering, and we
have to be worried about intelligence.

If that is something of concern, then I think
those people who are interested in it have to be better educated about
what it is that memory is and what can be expected from such
manipulations.

And finally on this, there's a huge
caveat. I'm now going to question the assumption that I made at
the very beginning, that if memory is good, then more is better.

Well, more is not better. At the extreme more
is worse. There are two famous cases, one a fictional case of
"Funes de Memorias" by Borges, a short story in which Funes
was capable of memorizing everything that was presented to him, and he
remembered everything that he encountered such that towards the end of
it he said, "Sir, my mind is like a garbage heap. It's all
there."

And over 100 years ago the famous psychologist
William James, in whose hall Dr. Schacter lives, said that to remember
everything is as valuable as to remember nothing because it's all
there and needs to be sorted out.

Now, there's also the case written in
Luria's book, The Mind of a Mnemonist, which you can get at your
local Border's bookstore, a subject that he studied for many, many
years. This was a subject who could memorize very well. He memorized
by using synesthesia, by mixing the senses which enabled him to
remember better, and he could remember very detailed information for 15
years, very precise knowledge of what numbers were given to him in what
order over a 15 year period of time. He had a very unhappy life and
ended up a failure.

I also had a subject. Up popped on my E-mail
one day as the Director of the center, "I have a memory problem.
Would you talk with me?"

And I sent back, "This is not a memory
disorders clinic. I can direct you to one."

"No, I have a kind of a problem you might
be interested in. Would you at least talk with me?"

And this was a young woman who claimed that she
had such a powerful memory that it interfered with her daily life, and
could I at least listen to her and direct her to someone who might help
her, and I had trouble at first understanding what she meant by that.

So I got out the two books that were published
at the millennia about all of the things that happened in the last
hundred years and just randomly opened pages, and I couldn't stump
her. I just randomly opened pages, and several times she said,
"Well, you have the date wrong."

And I said, "No, no, it's written
right here. It's a date line out of a newspaper."

"No, no. That's the date in which
they wrote it. The date of the occurrence was three days before
that," and so on.

And I said, "Well, how did you do in
college?"

She was a C student in college, barely made it
through, and I said, "Well, why couldn't you put this
extraordinary capacity of being able to remember to good use?"

She said she never could because it's
disorganizing. "I'd begin to do something and somebody would
say, 'Well, it's Thursday,' and I'd begin to go
backwards, Thursday last week, the week before, the month before, the
month -- five years before, and it's just like going through a
Rollodex, flip, flip, flip, flip, flip, flip, like that," and she
was distracted from what she was to do because she had such a powerful
memory.

Now, lest you think I'm making this up, we
also have her diaries, which she kept over all these years, and with
the help of an assistant, we are able to check information that she
said that she has by going through her diaries, and we have yet failed
to find any error or any mistake.

Here's a failed person in life who has an
extraordinarily strong memory for events that occurred in her life.
She's unable to use that, and the only way she used it productively
was she worked for a while with a very well known trial attorney, and
she was the assistant standing there or sitting there so that when some
claim was made about something happening on a certain day and it rained
that day and so on, this trial attorney could turn to her and say,
"Did it rain on that day?" And she could say yes or no
without having to go to the records and see. That's all that she
was good for.

So a little, maybe a little is good, but I
don't think any of us would want to have the memory of Mr. S, Mr.
Luria's patient, or Funes, the Memorias, the fictional character,
or the subject that I've worked with.

Now, let me turn a little bit to the research
on drug enhancement of memory, which is my special interest. This was
all started in 1917 by a study by Karl Lashley, a very famous
neuropsychologist, in which he gave a drug, strychnine sulfate, which
many of you know to be a rat poison, to rats each day shortly before
they were trained on a simple, little maze, and he found that they
learned the maze faster.

Now, this was of interest to me many years ago
because we thought we knew something about the mechanisms of
strychnine. So in the mid-'50s, with a colleague I replicated and
extended this study and found that, yes, strychnine did what Lashley
said it did.

But we couldn't draw the conclusions that
we'd like to draw, which has to do with the drug making memory
stronger, because we're confronted immediately with what we know is
a classic learning performance problem. The animals learn better. The
drug influenced the learning, but did it influence the learning because
the animals could smell better, because they were more attentive,
because they were more reluctant to enter alleys and so they were more
selective? All kinds of performance factors.

Now, if one is only interested in having human
performance better, then one doesn't care about this distinction.
That is, if you just want to get humans to perform better, you
don't care whether they remember better, whether they're more
attentive, or whether they're more highly motivated or whatever.

But if you're interested in mechanism,
it's very important. So I introduced the procedure of injecting
drugs not before learning, but immediately after learning, and the
reason I did that is because it had already been established or already
been suggested that when you make a new memory, there's a period of
consolidation in which the formation of the memory is susceptible to
influence.

This was first seen with electroconvulsive
shock so that humans and animals that are given electroconvulsive shock
treatments remember less well those things that happened just before
the treatment, and this and other things led to the view that memories
consolidate over time.

Now, if that's the case, I said it should
be possible to give a drug after the animals are trained and find the
same effect, and, lo and behold, I did.

Now, that led me and many others down a path of
using this post training drug injection procedure to find out which
drugs would enhance memory, which would not, where they acted in the
brain, and what mechanisms they used in acting in the brain to produce
these effects.

And I won't bore you with all of the
details. Suffice to say that we know that there are several brain
regions that are very important, and for those of you who are
interested in neuroanatomy, they include primarily the basolateral amygdala. They include the hippocampus, the entorhinal cortex, and
the medial part of the prefrontal cortex, in particular, but there are
some other regions as well.

We can enhance memory in laboratory animals by
microinfusing microquantities of the same drugs that we would inject
peripherally into specific regions of the brain and get exactly the
same results or we can put antagonists of those drugs directly into
those brain regions and completely block the memory enhancing effects
induced by peripheral drug injections. So this is a way of learning
about the anatomy of memory, the pharmacology of memory, and the
neuromodulatory systems that are involved in memory.

Now, interestingly many of these drugs converge
on promoting the release of noradrenalin, norepinephrine or acting on
the receptors that adrenalin and noradrenalin use because if we use
blockers of those compounds or of those neuromodulatory influences, we
can prevent the memory enhancing effects.

Now, we asked then a number of years ago why is
it that we have a brain that's organized in such a way as to be
labile to influences that happen after learning. Why is it your and my
brain is made that way?

Because I can skip ahead and say some of the
same drugs have been studied in humans. Amphetamine, for example,
given post training to humans will enhance memory just as it does in
laboratory animals. Well, why are our organs organized this way?

We came up with the idea that this might be
part of the selection process that enables us to keep things that are
important to us and not clog up our brain like Mr. S in Funes, the
Memorias with things that don't happen. It's a way of allowing
a period of time for selection.

So you have an experience, and a decision has
to be made. Is this memory to be kept or not?

Well, we ask what is it that ordinarily would
act in the body that does the same things that drugs do? Well, what
happens when you get excited? You release stress hormones to
yourself. We all do that.

When you are aroused, when you are insulted,
when you're frightened, you release adrenalin into the blood stream
from the middle part of the adrenal gland, and you release cortisol
from the outer part of the adrenal gland. They go into the blood
stream. Both of these stress hormones are released.

So we ask the question then: do the stress
hormones do the same things as the drugs? And the short answer is,
yes, they do exactly the same thing, and they work exactly in the same
places in the brain, and they use the same mechanisms that I describe
for the other drugs that work on GABA systems and noradrenurgic
systems, and so on.

So here's a built in system that does the
job, and our conclusion is that what happens with this release is that
a correlation is then created between the significance of an event and
the subsequent remembrance of the event, and I'll come back to that
a little bit later.

Finally, there's a caveat in all of this
research, which is very important to think about whether it's drug
manipulation or whether it's genetic manipulation, and that is if
there is simply a tradeoff between a drug and additional training. We
have found nothing that a drug can do that additional training
won't do.

So it's not as though the drugs turn the
animals into super animals. It just means that they get there a little
faster. That is, it gives them a little edge in how they get to that
point. That's very important to think about because if you're
thinking about outcome, then there's lots of ways to get that
outcome. You don't have to give a drug to get the outcome.

If you have a child that's not learning
well, you don't need to give it a drug. Give it more training to
get to the same outcome. Now, if you want to use a drug as an aid to
get to that outcome, then that's a decision that you have to make,
but it's not going to get you someplace that you otherwise
wouldn't get.

For example, Mr. S could do all of these
marvelous feats of memorizing. Well, we know perfectly ordinary people
who have been trained to memorize a telephone book. You can do that.
I mean if you want to spend your time learning a telephone book, you
can do that. I wouldn't particularly advise that unless you had
some special reason for doing so.

All right. Let me turn now more specifically
for a moment to the effects of drugs used in the treatment of memory
disorders, and here we have a sad story.

Despite many millions and millions and millions
of dollars that have been spent by pharmaceutical companies and biotech
companies, and despite a lot of academic research, we only have one
class of drugs that is useful in treating Alzheimer's disease.
It's all the same class. They're all acetylcholinesterase
inhibitors, which means that they inhibit the enzyme that destroys
acetylcholine when it's released. If you inhibit that enzyme, then
this neurotransmitter, neuromodulator is around at the synapse for a
longer period of time.

And the drug such as Tacrine, Aricept, Exelon,
and so on, they're all "me, too" drugs. They're all
acetylcholinesterase inhibitors, and the further development is to try
to get rid of the gastric distress, all of the cholinergic side effects
that one would not want to have, and they are more or less effective in
doing that, but they are not horrendously effective drugs.

As a matter of fact, they're modestly
effective. The underlying problem is that Alzheimer's disease is a
progressive disease. Subjects are going to get worse and worse and
worse no matter what you do, and all you can do is squeeze a little bit
more effectiveness out of a patient for some period of time. It is no
cure.

And -- and this is a tough one -- no new or
novel drugs have been produced. So there isn't any drug out there
which is a novel drug, which has been found to be effective, and there
have been a lot of them that were this close to being effective and
didn't make it all the way through for one reason or another.

There are lots of them that have been developed
by pharmaceutical companies that are very effective in animal models,
and then they drop out along the way because of side effects. I'll
just give you one odd ball side effect. There was a company that I was
consulting with that had a very powerful memory enhancing drug in
laboratory animals, which means they could learn much faster, not ever
better, but much faster, and it was yanked out because in Phase 1 it
caused nosebleeds in humans. So it was kicked out because of that, and
others have liver damage and they have other things.

They just haven't made it through for
whatever variety of reasons. And I was wrong because a dozen or so
years ago because so much money was being put into it, I bet that
we'd have three or four by this time working on different classes,
that are different classes of drugs working on different systems, but
they don't exist.

What's really needed when you look at it
carefully in disorders such as Alzheimer's disease is not the
palliative types of drugs we're talking about that squeeze a little
bit more out of a deteriorating brain, but we need drugs that will or
some treatments which will prevent the disorder from occurring in the
first place or restoring cellular function through some other means if
that's possible to do so.

And there is an awful lot of effort going on at
the present time, and now I switched my bet, and my bet is that these
are going to pay off. Let's say, in the next ten to 15 years
we'll have some treatments which might -- particularly because so
much more is known about the etiology of Alzheimer's disease that
it's a good bet that something will happen in that area.

All right. Now, let me say a few words about
blocking memory formation. Can we block the formation of memory? The
answer is, yes, we can do that.

I already mentioned that electroconvulsive
shock will do that. That's been known since 1949 approximately,
and it's known both for humans and animals that if you give such a
treatment, there will be a selective forgetting of things that have
just been learned.

But there are also a lot of drugs that are in
common use that are antagonists of memory that impair or block memory,
and I'll mention some of them. Anti-cholinergic drugs will do
that, drugs like atropine and scopolamine will prevent memory
formation. There's not much danger of that happening because
these drugs are not used in high doses ordinarily, and they're not
anything that's subject to abuse, by the way. These drugs have
such unpleasant side effects that you wouldn't find many people
abusing them.

But there are others that are abused.
Benzodiazepines are memory impairing drugs, drugs like Valium, Halcyon,
clonazopam. All of these drugs induce anterograde amnesia, in both
humans and in animals, if these drugs are taken in high doses.
Performance can be reasonably normal without registering the
information acquired while under the drug. This is anterograde
amnesia.

And these drugs certainly will weaken the
formation of memory, and in some cases they will have very powerful
effects, and these are drugs that are commonly taken by many of us.
They were anti-anxiety drugs originally, but we apparently have lots
of anxiety because they are sold in vast amounts throughout the world,
much vaster, I think, than the extent of anxiety.

So benzodiazepines are there, and interestingly
they work in the same place in the brain that I talked about. They
induced their amnesia by acting specifically in the basolateral
amygdala. So there's something about that region of the brain
that's integrating an awful lot of neuromodulatory influences
coming in, including those for the benzodiazepines.

In the last category are the beta blockers,
which are commonly used for the treatment of heart disease, and
I'll say a little bit more about those.

This work came out of the work in my laboratory
with laboratory animals in which we found that a common effect of many
drugs that enhance memory had to do with the activation of the
noradrenergic system within the brain and then this particular region
of the brain and some other regions as well.

So it looked as though with that information
and the information that we had from the stress hormones that it might
be that ordinary emotionally aroused memory, the memory of emotionally
arousing experiences might involve the systems in humans.

So Larry Cahill, a colleague of mine in the
laboratory, set out to do this. We did the following study, which is
now well known in the literature.

He told human subjects a story about a boy, and
it had two versions. One is an emotionally arousing story, and the
other is a boring story. And then he measured the memory in a surprise
memory test three weeks later, and the subjects selectively remembered
better the information presented to them during the exciting part of
the story.

So let me run through it for you. A boy and a
mother leave home and they cross the street and there's a slide.
There are 12 slide that are shown. Cross the street. They see a
damaged -- I'm giving you the boring story -- they see a damaged
automobile. They visit father who works in the hospital. They're
having disaster prepared in the demonstration that day.

They see people with make-up on to make them
look like they've been injured. The mother makes a telephone call
and goes to the bus and goes home, and that's the story.

And you can divide it into three parts. Early
stages, leaving home, in the hospital, and then the denouement at the
end.

On the surprise memory test three weeks later,
the subjects remembered all three parts equally well.

Now, other subjects, exactly like those, were
told a different story, same 12 slides, and the test is on what's
in the slide. Told the same story.

The boy and a mother leave home. They cross
the street. The boy is hit by the car. He's seriously injured.
They rush him to the hospital.

Surgeons work frantically to save his life and
reattach his severed legs. A distraught mother makes a telephone call,
goes to the bus and goes home.

So here it is. Same pictures, and then the
surprise memory test is: tell us what you saw in the picture.
Don't tell us about the story. What was in the pictures?

And there is a significant increase in the
information remembered in the pictures in this subjects that had the
exciting story told.

So then Larry and I did the same experiment,
except we gave the subjects a beta blocker, Propranolol or Endurol, in
clinically used dose, in a clinically used dose, and told them the
story, and then tested them three weeks later, and those subjects were
-- their memory was just like that of subjects that had received the
boring story.

So here's a blocking of emotionally
influenced memory by Propranolol. Now, this turns out to be important,
we think because it has some implications for the etiology of post
traumatic stress disorder, and as you may know, about 25 percent of the
Vietnam veterans had or have post traumatic stress disorder, and any
time there is crisis, traumatic event, there can be a significant
amount of this disorder, which in many cases will never go away.

In some cases it will go away in a few months,
and what Roger Pitman did was to get hold of human subjects that had
been traumatized in an accident or in some way and put them on beta
blockers as quickly as possible afterwards and maintained them on for
several weeks and then looked to see symptoms of PTSD several months
down the line.

And a first study that was just published
showed that there is a significant decrease in the expression of PTSD
several months down the line, and subjects were put on the beta
blockers.

Well, what is the logic of this? After all,
the exciting event is over.

The logic is based on the evidence from studies
of post traumatic patients, that the events will flash into the mind
after they're over the next day and the day afterward, and you
consider each one of these as a rehearsal.

So every time they relive the experience of
being mugged or being raped or being almost killed in a car or
whatever, every time that comes up again, there's the same
emotional reaction again. It's like a rehearsal with the autonomic
concomitance of this, and the effect of the propranolol is to allow
this inadvertent rehearsal, but without the stress hormone consequences
of that, which would lead to a strengthening of the memory.

There's another study in press that shows
the same results. So there now will soon be two studies showing the
effects on PTSD. Whether this will hold up in the long run we
don't know. This is very early in this research.

Now, let me bring up very quickly some issues.
You asked me to, some issues that might be worth discussing, and one is
the blocking memory. I'll start with that because that's where
we just finished discussing, and there is some concern that it might be
a bad thing to reduce the strength of memory for people who have had a
traumatic event for lots of reasons.

Maybe we need to remember trauma in order to
deal with life or maybe we need to remember the trauma in order to
testify in court, and so on.

So one could make an argument that it is
certainly a judgment to be made as to whether if this really does work,
as it appears to, but we're not sure at this point; if it really
does work, then one would have to make a judgment. Is it better to
reduce the probability of development of PTSD and forego a strong
memory, or is it better to save strong memories, complete with the
suffering, and forego the opportunity to decrease the suffering?

That's a judgment call that each individual
would have to make if what I have told you turns out to be validated
and substantiated.

Here's another one that's of deep
concern to me, and this is, by the way -- we've had several
conferences on this topic, including one at the Ciba Foundation in
London a few years ago, and so we've discussed these issues many
times in small conferences.

This one concerns me. Arresting
neurodegeneration, I said that there were likely to be such drugs.
I'm worried about that because I could anticipate a situation in
which Alzheimer's disease was identified, let's say, because a
person is becoming demented. Now there's a drug which will prevent
any further deterioration, and now you have an arrested dementia, which
means that people will be in this arrested state for a longer period of
time.

It is not necessarily the case that you would
want to stop deterioration if the deterioration is far along. Once,
again, that would be a judgment call.

The next one I touched on, drugs for children.
If we go down that slippery slope from Alzheimer's disease to age
related declines in memory to drugs for normal people who would like to
have an edge, well, children can be normal people who would like to
have the edge. They would be on that slope, and so the question would,
in the subjunctive, or will, if things have a certain way, come up;
should drugs be given to children as an ancillary treatment for
learning? Why? Which children? Is this going to be another economic
divide? The rich kids get the pill in the lunch box and the poor kids
don't, if it's readily available.

I mean, I can certainly foresee that
happening. I can't predict that it would happen, but I can foresee
that happening. And is this yet another cost that we're going to
have to bear in society in treating the walking well?

We already spent a lot of money on treating the
walking well. Here's yet another example of it.

And finally, the worst one of this is the
designer baby and what I call the Time magazine issue. Time magazine,
based on this study that was published in a very reputable journal took
unfortunately a word that was used in the paper, both in the abstract
and in the introduction of the paper, "intelligence."

That PET study did not study intelligence.
That study asked does a mouse freeze when you put it in a place where
it had received a shock. Does a mouse swim more rapidly to a platform
where it could escape from cold water?

The genetic manipulation produced mice that
both of those did better than their controls. That's what they
did.

Now, there's nothing in there that 100
other people haven't already done with drugs. Those are the same
studies that have been done literally hundreds of times with drugs,
enhancing memory of this kind. So there's nothing conceptually
new.

What's new is the permanence of it and the
use of molecular genetics to produce it, which leads people to think,
and Time magazine certainly thought that and the author of the paper
implicitly suggested that by using the word "intelligence"
rather than "memory" or "performance," that it
might be possible with right consultation of the right people to have
designer babies in which you insert particular genes which are
guaranteed to make them learn better.

Well, there's no guarantee, but my guess is
that we would have, if they worked, we'd have more Mr. Ses and more
Mr. Funes de Memoriases and not necessarily more thoughtful,
intelligent human beings that will help to make this place a better
world.

Thank you.

CHAIRMAN KASS: Thank you very much.

We should just open the floor for discussion.
Mike Gazzaniga, please.

DR. GAZZANIGA:: Thanks, Jim. That's
terrific.

It might be helpful though for us to have you
distinguish between memory as sort of a unitary event and memory as you
and I know it to be, which is this complex system of information and
coding, retrieval and all of the rest.

The reason I say that is that one of the
benchmark observations in the clinical and neuropsychology is that the
memory quotient score correlates perfectly with the IQ score. And so
when we have these enhancing devices that allow for, quote, increased
memory, probably what we mean by that is increased sort of lexical
entries or something. It isn't enhancing the entire memory system
that allows the intelligent encoding and retrieval of all that
information for use.

And if that pill came along there might well be
an impact, it would seem to me, on these matters. What do you think?

DR. MCGAUGH: Well, starting way back when I
first began working on the drug enhancement, I tried to ask the
question are there limits to the kind of information that, let's
say, post training drug injections will influence. And the answer so
far is no. That is, I found memory enhancement with post training
administration of a variety of drugs in every task that I could think
of that would tap different kinds of information that the animals were
acquiring.

So it appeared to be general over a very broad
range. Now, we're going to hear more about different forms of
memory in the human this afternoon, but as far as different kinds of
things that animals are capable of being taught, I haven't found
any constraint on that, nor has anyone else.

Now, with respect to the memory and the IQ,
however, wouldn't you agree that if the memory test was a perfect
predictor, then you wouldn't need the IQ test, and the IQ test
covers things besides just the memory subtest, correct?

DR. GAZZANIGA:: Oh, yes, yes. The fact is
though that if you take a look of somebody with an IQ of 100 versus an
IQ of 125, the memory subtest goes right up with it.

DR. MCGAUGH: Sure, sure, and it would have to
because that's the way it was built.

But one final point. Beta blockers and
Baghdad. So let's say you're going to send troops into
harm's way. Is in some sense modern neuropharmacology suggesting
in order to prevent post traumatic syndrome you ought to give them a
beta blocker before they go in for their dirty work?

DR. MCGAUGH: Well, first let's assume that
what has been found will be replicated. Let's make that case. I
don't want to make that too strongly because this is an early stage
in the human application.

But once again, that's your tradeoff
question, isn't it. Let's suppose they really were to prevent
or to attenuate the development of post traumatic stress syndrome, and
actually the number from Vietnam, I think was 29 percent of the
veterans of the Vietnam War had post traumatic stress syndrome, from
which many never recovered, and then they filled up the veterans
hospitals. That's just a fact of life.

Would it be worth using pharmacology to prevent
that from happening, if it didn't do anything which would harm the
person? That's the judgment to be made. Somebody would have to
make that.

DR. GAZZANIGA:: That's right.

DR. MCGAUGH: Now, stimulants have been given
to soldiers for years to make them implicitly, and I think explicitly
in some cases, to make them better soldiers. Nicotine is a memory
enhancing compound in laboratory animals. Post training injections of
nicotine enhance memory. It just does. It's been known for many
years.

One doesn't do those studies in humans
because of the taint from the tobacco industry so that one just
wouldn't do that research. You don't want to be tagged as
somebody who's going to increase tobacco sales, but my guess is
it's probably is memory enhancing in humans as well, and caffeine
as well.

Soldiers are routinely given cigarettes, and
that came in with their K rations. Amphetamines were used by the
Germans, given all the time to their soldiers.

So the use of pharmacological enhancement of
human performance is not new to the military. So the question is if
you think that they're going to survive and they have a quarter
percent, a 25 percent chance of being debilitated even if they win,
would you want to do something to prevent that from happening?
That's a judgment that would have to be made.

CHAIRMAN KASS: Gil and then Dan.

PROF. MEILAENDER: I don't know I even know
enough to know how to ask my questions here, but I have two sorts of
questions. One is -- and this is really a naive layman's question
-- but in some of the things you talked about with respect to --
actually it was particularly with respect to sort of blocking memory
formation, which it seemed to involve controlling various kinds of
emotional responses that one might have in various ways.

In what sense is that -- in what sense were you
doing something that specifically touches memory when you do that?

I mean, I don't know. As I say, this may
just be too naive, but is it really memory that one's dealing with
at that point? That's my one question.

Let me just ask my other and you can do what
you want with both of them.

Is it conceivable just in terms of the
mechanisms one's working on that one could go to work on
Alzheimer's, on trying to find ways to stop that kind of
degeneration, that would not also be applicable to, you know, possible
memory enhancement in school children, say, or something like that?
Are these separable categories?

So those are my two questions.

DR. MCGAUGH: Well, those are both very good
questions, but I do think they are completely separable from my
perspective. Let me take the first one.

The answer is no. We're not only affecting
memory. The question is are we affecting memory, and the answer to
that is yes. We can show that it's not due to some other side
effect of it.

We are affecting memory, but we're also
affecting -- I mean, after all, these beta blockers are going to affect
the action of the heart. I mean, that's what -- think of all the
things that adrenalin are required for. They're required for
releasing glucose from the liver and so on.

So that when we give a beta blocker, lots of
systems are going to be affected. The body is going to be changed in
lots of different ways, but we've been able to sort out with our
experiments the question is it specifically, no matter what else
it's doing, is it working on memory, and the answer is, yes,
it's working on memory while it's doing all of these other
things.

Does that answer that part of it?

All right. The second one is that I think that
they're really quite different questions. Let's take the
Alzheimer's disease, and let's assume for the moment that the
cause of it is the anatomical sequelae that lead to these plaques and
tangles in the brain. Let's just assume that for a moment, and
that's still a little contentious in the field.

The kinds of drugs that one would use for that
would be the ones that would interfere with the cellular processes that
lead to that kind of neuronal damage, and they may have no other
effects. They may have no other effects at all. They just may prevent
that sequelae from taking place.

Whereas the drugs that are currently given for
Alzheimer's disease, the acetylcholinesterase inhibitors, make
better use of a declining brain system that uses acetylcholine as part
of its communication mechanism, makes better use of that, but it
doesn't do anything that we know of to stop the degenerative process.

So the degeneration is continuing, and it's
sort of like trying to squeeze a little bit more lemon juice out of the
lemon juice that's been squeezed. You can always find a little bit
more.

It's like the economists who say that we
are never going to run out of oil, and their reason is because there
will always be some oil. Now, we'll never run out of coal because
there will always be some coal.

Well, there will always be some acetylcholine.
Can you make it work better with a declining brain?

But the drugs that are used to make the
acetylcholine work better or whatever neurotransmitter may do nothing
at all to deal with the underlying cause of the disease, whatever that
may be.

So I see them as going in different
mechanisms. To put it in another way, I don't think that
there's any danger that normal human beings will run out and buy
Exelon or Cylert or one of the other Alzheimer's disease to try to
make them a better sales manager. That's not going to happen, and
those drugs are not going to be given to children. I mean, nobody in
their even quasi right mind would think of doing that, nor if there
were drugs that would prevent neurodegeneration would a normal person
take them unless they thought they were at risk for the degeneration,
which brings up another question.

If we were able to make those predictions,
would there be drugs to deal with that?

CHAIRMAN KASS: Dan Foster.

DR. FOSTER: Just a comment and then my
question.

Of course, the Alzheimer syndrome or disease is sad, but the sadness and pity is not so much for the patient, who doesn't remember anything, but for the caregivers. The caregivers are continually stressed and presumably releasing epinephrine and norepinephrine all the time. Maybe that is what keeps them going. It is not a bad disease for the patient when fully developed because memory is gone, but one wants to prevent it if at all possible.

Now, you just made a statement which I was
going to follow up. You said that even if you knew that there was a
drug that was going to be preventive, let's say, of the
Alzheimer's dementia, as an example, would I take it or would you
take it, and the answer might be if that were solely an effect of the
drug that you would not. You don't have a family history of
Alzheimer and so forth.

But one of the things that there's an
increasing interest in in medicine, I believe, is where a drug which is
used for one reason has powerful effects in others. For example,
probably the cheapest and safest chemopreventive drug that you can take
with the rare exception that you're going to bleed is an aspirin.
It's going to cut colon cancer 50 percent, probably going to
diminish, slow down Alzheimer dementia. You know, it's got a
variety of things that are additional.

Now, one of the drugs, and I'd be
interested in your comments, that's been very much of interest
lately in terms of chemoprevention of the Alzheimer dementia are the
statins, the drugs that are used to lower blood cholesterol. I mean, at
least in terms of retrospective studies, if you've ever taken them,
you may be as much as 70 percent in large populations. The veterans
population study is the one I know best.

It also is very helpful, it turns out in odd
ways of preventing osteopenia in women, bone loss, and of course, the
people who really work on cholesterol, we have two guys that are Nobel
Laureates for cholesterol at our place. They believe that, you know,
to take a target of a cholesterol of 100, let's say, even if
you've got diabetes and so forth. The NIH says 130 LDL, the bad
cholesterol.

They clearly show a linear progression back to
the 60s and so forth. In other words, if your LDL is 100, that's
great, but if it's 60, it's better if you want to prevent
atherosclerosis and so forth.

So the question would be: would you have the
same anxiety about a single prevention for something like dementia if
at the same time you could handle -- and this is before they get a
disease. So you're in prevention and not treatment. Would that
change your thought about the approach to this fairly common problem?

I guess I don't know whether I'm saying
this very well, but if you get several effects from a drug that's
relatively cheap and seems to be -- and I don't want to confirm
that it's really stopped. It's not due to the cholesterol.
That's clear. It's not due to the cholesterol even though E4
-- I mean apolipoprotein, E4, E4 is one of the genetic risks for early
Alzheimer's and so forth, and that also gives you lipid disease, as
well.

But if you could do that, would you have the
same concern about it?

DR. MCGAUGH: Well, let me shift diseases to
Huntington's.

DR. FOSTER: Okay.

DR. MCGAUGH: There it's clear. If there
was neuroprotection for Huntington's disease or for
multiplesclerosis, I don't think there would be any question at all
because they're well understood or pretty well understood.

DR. FOSTER: Sure.

DR. MCGAUGH: But at the present time, in the
case of Alzheimer's disease, it's etiology is not well
understood even though we know that there are genetic predictors of it,
and so it's not clear what one should do.

You know, take ten times the amount of Vitamin
E and take more aspirin and all the rest, statins, whatever. If I had
three of the genetic markers for Alzheimer's disease, I probably
would look for all of the above in order to keep that from happening,
just as I would if I were destined to have Huntington's disease do
everything I could to find out how I could be neuroprotected.

Now, let's think about it more broadly,
about the general public where they're not going to have genetic
information about this. Already people are taking Vitamin E. People
are taking aspirin, I mean, much more than they used to. So there are
people who are trying to be neuroprotective just to cover the odds.

Now, let's suppose it costs $100 a day to
be neuroprotected. What do you think would happen to the Vitamin E
sales and the aspirin sales and so on? They'd go down to the floor
because people would say getting that new car today is more important
than what happens to me when I'm 70 years old or 80 or whatever.

So there are huge economic consequences that
have to be factored into this, just as there are economic factors for
dealing with AIDS, for example, or the cost of the medication
influences how well it's point to be accepted and used in different
countries and so on.

So the same thing would apply in the United
States. The cost of these things, even if you knew their
effectiveness, would have a big influence.

DR. FOSTER: I was just really trying to get
to the issue that sometimes there are surfaces, and we've heard a
little bit of it today, that if you do anything to alter the natural
development of nature, that is to say if you -- I'm not talking
about acute disease or, you know, a kid who gets zapped by a sniper or
something like that -- but if you alter it, that that is both -- it
should not be done. The playing God syndrome.

And I just want to be sure that your worry
about the issue of the side effects and so forth of dementia did not
imply in some sense that if scientific investigation could give us
prevention against some of these major things and at a reasonable cost,
which also has to be taken that you -- I just wanted to be sure I
understood your philosophy about that, and you've just answered it,
but I wanted to bring that to the floor.

DR. MCGAUGH: And I think in the case of
neuroprotection that that's likely to happen. I mean, that's
the greatest effort that's being made at the present time on
finding neuroprotection, even some thinking that it might be possible
to make the cells behave better and behave the way they're supposed
to after they have started to degenerate.

So not only protection, but recovery are two
targets that are being actively pursued at the present time.

What I was trying to say though is that this is
quite apart from the other reasons for having drug enhancement of
memory, quite separate.

Thank you.

CHAIRMAN KASS: Could I clarify? I was in
the queue. I've also got Janet and Paul.

I would like to clarify just the bottom line on
what is currently available or likely to be available in terms of
interventions both for enhancement and for blockage.

I think I heard you say that notwithstanding
the huge amount of effort, we have nothing really available with
respect to the already existing degenerations of Alzheimer's
disease.

Nevertheless we do have in animal models
various kinds of things that can enhance memory at least as testified,
the performance of certain kinds of tests, but that the attempt to use
these things in human beings have run afoul because of side effects in
most cases.

Let me add one additional fact that you alluded
to at the beginning, but stayed away from. As I understand it, the
main interest in the biotech companies or the others who are pursuing
this is less Alzheimer's disease, but much more the memory
enhancement --

DR. MCGAUGH: Yes.

CHAIRMAN KASS: -- of -- I can't find
the keys.

DR. MCGAUGH: That's where the market is.

CHAIRMAN KASS: That's where the market
is and enhanced probably further by the market of the people who want
their kids to do better on the SATs or as you have it.

With respect to those things, is there likely
to be something -- if you leave aside the treatment of the
degenerations, but talk about possible things that would be coming in
the area of the potentiation of more or less normal memory or this new
age related; is this 20 years, 30 years or --

DR. MCGAUGH: Well, we always think it's
right around the corner because so much money is being spent doing
exactly that.

I did send in a tape [to the Council Staff] of a BBC program that is about ten years old. It's available from somebody here, and in it I was interviewed, and I said
that my belief was that the real target of this drug development was
not for the memory impaired, but it was for the normal because
that's where the market is, but nobody will say that.

I'll be damned if they didn't find the
Director of Marketing of a major pharmaceutical company that they put
right after my statement who said, "Yeah, that's what
we're going after. That's where the market is."

I mean, he just said what I said that nobody
would say in public. I mean just opening.

Well, their compound failed. They put a lot of
money into a compound, and it just didn't work.

Now, let me back up here and say there are
things that work, but they have no interest because there's no
money in them. Paul Gold has shown that glucose enhances memory, not
only in normal people, but in elderly people and in Alzheimer's
patients. You get a little improvement with glucose, but there's
no money to be made in that.

Amphetamine is a very potent memory enhancing
drug, as I mentioned, both in humans and in animals, and it works even
when injected in humans or given to humans after they've learned
something. It strengthens consolidation.

But there's no money to be made in
amphetamine, and besides that, it's a nasty drug, and people get
dependent on it and they get addicted to amphetamines.

So there are things right now that people could
take that will enhance memory, but pharmaceutical companies are not
very interested.

Now, one major company, Abbott Laboratories,
certainly knew about nicotine. So they decided to modify the nicotine
molecule and, once again, the count was millions of dollars to make a
drug that is like nicotine, but for which they could get a patent, and
it didn't work all the way through Phase 3. So that was a big loss
of financial investment.

Now, nicotine probably works, but it's also
addicting. So there are these side things, the things that might do
something for memory that we know of or that companies have tried to
develop. All have some kind of a restriction. They just --
there's no free memory enhancement that isn't going to do
something else.

It's sort of like looking for a
nonaddicting opiate. You remember in the early part of this -- well,
right at the turn of the last century when heroin was introduced by
Bayer. It was called Heroin because it was
heroic. That's why they called it that, as the nonaddicting opiate
for children, and it was in children's cough medicine for probably
20 years.

And after the discovery of the opiate receptor,
there was a huge increase in looking for nonaddicting opiates. If we
could only take that drug which is analgesic and modify it, you know,
pull off a methyl group here, add another group over there; we'll
find an opiate that is nonaddicting.

Well, the less analgesic it is, the less
addicting it is. So memory enhancing compounds, let's say, our own
memory enhancing compounds are adrenalin and cortisol, and they do all
kinds of things. I mean, you wouldn't want to give adrenalin to a
heart patient, for example, but we know that if we give adrenalin to a
rat or a mouse, we can make it learn a lot faster or if we give a drug
that will activate those receptors it will happen.

But there are always going to be these side
effects, and I don't see them disappearing, but that's what the
pharmaceutical companies are looking for. They're looking for the
pure memory enhancing drug that doesn't do these other nasty
things.

And is that around the corner? Maybe it will
be in the paper tomorrow. I don't know.

CHAIRMAN KASS: On the parallel side now on
the memory blocking, the same answer?

DR. MCGAUGH: Well, that can be done right
now. I don't think --

CHAIRMAN KASS: But also with drugs that
have systemic effects, right?

DR. MCGAUGH: Yes.

CHAIRMAN KASS: I mean blockers are also not
innocent --

DR. MCGAUGH: You pay for it, but let's put
the emphasis. You want to reduce the anxiety, and so you take a
benzodiazepine. Well, the sufferance there is that you are also likely
to induce anterograde amnesia. It was discovered after it was approved
for anxiolytic effect.

So now you take, let's say, benzodiazepine
to produce anterograde amnesia. The payoff is you're going to be
less anxious. I mean, you don't have to remember.

(Laughter.)

DR. MCGAUGH: I mean, the way this -- many of
you here probably know that it was discovered by psychiatrists and
psychologists after the benzodiazepines were introduced. People would
come back after having been on a trip, and they were very anxious about
going, and they would come back in the report, "I don't remember
what happened on this trip," and so that's what stimulated the
research on it.

And then it was discovered in animal models as
well as in humans it's a very strong anterograde amnesia, which of
course is dose dependent. So that you can certainly take a
benzodiazepine and get an anxiolytic effect without having severe
anterograde amnesia, but you can also take a high dose, and you think
you're okay, and then have anterograde amnesia.

CHAIRMAN KASS: Thank you.

I have Janet and then Paul.

DR. ROWLEY: Well, I want to follow up. My
question is in a sense related to what you just said because many, many
individuals are taking beta blockers, particularly older individuals,
and the question then is -- and I don't even know what doses are
generally used for beta blockers, but what is the relationship of the
dose that would be used clinically and that which causes retrograde
amnesia?

DR. MCGAUGH: The clinically used doses,
let's say, propranolol, 20 milligrams, is not going to induce any
retrograde amnesia. What it does in a study so far is simply prevent
the added memory that is induced by emotional arousal. So we have not
found in human subjects any memory impairment in these doses, but we
have found complete blockage of the effect of this emotional arousal on
subsequent memory. So in that sense I don't think there's any
danger.

This, by the way, independently in the same
year, an experiment was done in a very different way by Rob Jenson and
his colleagues in southern Illinois, but in place of emotional arousal
what they -- these were now with elderly people who are on beta
blockers or on other drugs for controlling heart disease, and they
taught them standard psychological verbal material.

And then after that they had them squeeze
what's called the hand dynamometer in which you squeeze it, and you
can see how much pressure is induced by squeezing it, and this is well
known to release catecholamines, including adrenalin. You do this.

And they found that the memory, squeezing this
thing, enhanced memory in the elderly subjects who were on other drugs
for treatment of heart disease, but did not enhance memory in subjects
who were taking beta blockers.

In normal subjects now, Larry Cahill has used
another technique which is standard procedure in cardiology studies,
and that is just thrusting one's hand into a bucket of ice water.
I know that doesn't sound very sophisticated, but it will certainly
get the heart going, and it releases adrenalin massively right at that
time, and Larry Cahill has now found that memory for ordinary verbal
material is significantly enhanced. Subjects learn something and put
their hand in this tub of ice water.

So it doesn't have to be an emotionally
arousing response, but we think in our nature that's probably what
ordinarily controls it because we don't go around putting our hands
in buckets of ice water to release catacholamines. We get
catacholamines release when people say, "You're dumb,
you're ugly, you're stupid. You did a good job. You won the
lottery. You got a Nobel Prize. You're going to be executed.
Things like that tend to get epinephrine or adrenalin released.

CHAIRMAN KASS: Paul McHugh.

DR. MCHUGH: Well, we could talk all afternoon
after that wonderful talk, Dr. McGaugh. I had two comments and then
one question.

The first comment was in your deep wisdom you
reinforced what my father told me when I first went off and recognized
that there were a lot of people in schools that were smarter than I
was. He said, "Don't worry. You can out work them."

DR. MCGAUGH: That's right.

DR. MCHUGH: And it's the truth.
You're backing that up.

DR. MCGAUGH: That's a missed point. My
neighbor, who wanted the drug for her child, I don't think had
asked the child to work a little harder. I think she was just saying
she's not doing well. Let's make up for that..

DR. MCHUGH: That's right. That was my
father's idea. Just work harder. You can do it.

DR. MCGAUGH: Well, he was right.

DR. MCHUGH: He was right in many things.

The other thing was, of course, in relationship
to treatments for the conditions, the deteriorating conditions like
Huntington's disease or Alzheimer's disease and the like, which
are devastating when they occur and which have their beginnings before,
if we understood not just the risk factors, but the mechanisms, it
probably would be that everybody who had those mechanisms in play would
probably take the treatments even no matter what they cost.

The real problem now is not for
Huntington's, but something like Alzheimer's disease. We only
know that there are risk factors that are tied to it.

DR. MCGAUGH: Think of all the people who are
taking Vitamin E and aspirin at the present time.

DR. MCHUGH: Oh, I'm well aware of that.
Aren't you?

DR. MCGAUGH: So that there is at least among
people who pay attention to these things -- we try to reduce our risk.
I mean, if we knew more about it, we could do more selective things to
reduce that risk.

DR. MCHUGH: That's right. So the
mechanisms would help us to know more things.

DR. MCGAUGH: Absolutely.

DR. MCHUGH: I had one real question I wanted
because it was very interesting what you were saying about the effects
of beta blockers on consolidation of memory. But as you know, lots of
people use beta blockers who are performers, particularly artistic
performers.

DR. MCGAUGH: Absolutely.

DR. MCHUGH: Stringed instrument players and
the like, and they discovered in their performance that they can do
much better if their hands aren't trembling and the like.

And I wondered about you making the point that
beta blockers inhibit consolidation. Do they have any effect on
retrieval, on memory retrieval, which would both affect the piano
player who was following the Schuman approach of doing it by memory,
but also might affect us otherwise negatively?

DR. MCGAUGH: I had a whole section on that
that I didn't include because of lack of time, but may I just say
something about that?

First of all, it is the case that beta blockers
are the drug of choice for stage fright, speech fright, and also for
controlling trembling and things of that kind.

But in the case of the violin player who is up
there performing, that is so over rehearsed that the memory is not
going to be affected for that. That's on automatic drive at that
point. So that's not an issue.

But these same hormones that I told you enhance
memory consolidation on other circumstances, on other conditions, will
impair the retrieval of memory, and we have studied that fairly
carefully using cortisol in the human or corticosterone in the rat, and
the experiments are as follows, and we try to make them as parallel as
we could for the two.

The subjects learned something on one day to
some criterion, and then the next day they are tested on it, and then
we check to make sure it's not interfering with their performance
or anything of that kind.

And it turns out that a glucocorticoid, a
cortisol, has an impairing effect for about one hour after it is either
released or after it is injected, and we know that it is the cortisol
because if we give a drug that blocks the release of cortisol, then
there is no memory impairing effect of the treatment or in a rats it
can be a shock, an electric shock to its feet.

And this is an effect that lasts for about an
hour, an impaired retrieval selectively induced by that. So we think
that all of the things that we have learned from our undergraduates
over the year about how they knew the information very well and they
just panicked on a test and couldn't remember it. We now think
that at least some of that may have been honest, that there was an over
excitement and there was a temporary depression of selectivity of
memory retrieval lasting for about an hour, and this we found both in
rats and in human subjects.

And we are now doing experiments at the moment
to find out the involvement of beta receptors, beta adrenergic receptors
in that mechanism. We had experiments in place right now doing that.
So I can't answer the question.

But in everything else I said it had to do with
getting information in and getting it stored. It all had to do with
making a memory, and now we're shifting it. That's why I left
it out of my main talk here. We're shifting to something else and
saying are there things that affect our ability to utilize information
that we have, and stress hormones do affect that.

DR. FOSTER: Just one quick question. Does
epi/norepi also do the same thing, that one hour impairment of
retrieval?

DR. MCGAUGH: No, we haven't examined that
yet.

DR. FOSTER: Because oftentimes they're
almost always up together.

DR. MCGAUGH: Yes.

DR. FOSTER: And you know that cortisol has a
permissive effect on that.

DR. MCGAUGH: And we're looking
specifically once again in the basolateral nucleus of the amygdala
because that was critical for our consolidation effect, and I can say
our first experiments indicate that activation of beta adrenergic
receptors within this same region of the brain plays a role in this
memory retrieval effect that I just described.

But that's not published. That's the
only thing I've told you that's not published yet.

CHAIRMAN KASS: Frank Fukuyama.

PROF. FUKUYAMA: Are you born with a certain
natural memory capacity?

And when you talk about memory enhancement,
you're talking about the ability to move information in and out of
that fixed capacity or can the capacity itself be affected by
environmental factors?

DR. MCGAUGH: You're probably going to hear
a lot of that, something about that from Dan Schacter, but let me just
touch it briefly.

The answer is no because there are lots of ways
in which as we go through life we improve our memory capacities.
Let's say in areas that are your hobbies or things that you deal
with an awful lot, you just get better and better because you have more
information that's related to other information, and it's not
stored as an isolated packet, but it becomes integrated.

So that I have two hobbies. I play jazz
clarinet and saxophone, and I do woodworking. So I have lots of things
that are very easy for me to learn because they are related to that,
but if somebody starts talking to me about their hobby which is
something I don't know anything about, I would have trouble
remembering it just because I don't have the contextual connections
formed to do that.

Now, also, if you take very specific domains,
memory can be trained. So that if you want to be able to memorize
digits, let's say for some reason you have a zip code which is
2,000 numbers long. You could do that. You could do that. And you
would be better then for a while in memorizing of digits. So that this
specific domain can actually be improved.

So you're not born with a capacity. What
we're born with is without any extra effort to get seven digits
plus or minus one, and that's one reason we had seven digit
telephone numbers and the area code was kept separate, because you can
remember seven digits at least long enough to write them down.

That's probably the native thing that most
people have, but you can have a digit span of 15 if you'd like to
have it for some reason. You can get special training to do that.

CHAIRMAN KASS: Bill and then --

DR. MCGAUGH: And, Dan, I hope that you'll
elaborate on that because that's more in your domain.

Excuse me.

CHAIRMAN KASS: Bill.

DR. HURLBUT: I want to ask you about something
you touched on briefly, the engagement of possible memory enhancing
agents in education. If you say that, as you more or less said or at
least implied strongly, that memories related to life significant
issues because the body itself produces through at least the adrenal
gland, and probably in many other ways, agents that modulate memory
retention. It then implies from that that if you enhance one component
of that system artificially that you might be disrupting the
psychophysical unity of your identity or your normal life processes.

In other words, you'd be forcing on your
system memory of things that your other normal process wasn't
encoding.

DR. MCGAUGH: Absolutely.

DR. HURLBUT: So in other words, we have a
therapeutic model of memory enhancement where we think there's a
deficit. That makes sense, and just as it's easier to fix a broken
link in a chain than it is to strengthen the whole chain, we can
comprehend how that might work where there was a problem.

But would you really improve life overall is a
large question I hear going on in the background of what you said. In
fact, you started at the beginning in saying if memory enhancement were
a simple good, then evolution probably would have done it. Didn't
you say something like that?

strong>DR. MCGAUGH: Somebody.

DR. HURLBUT: Okay. Here's my question.
The work that Mike Merzenich is doing with enhancing Ó- going back to
basic neural processing, things like dyslexia and reworking very
fundamental things in the way a person takes information where they
have a learning deficit or, for that matter, any strategy of
approaching life tasks.

He suggests that maybe you could combine what
he's doing now with computers with drug enhancement to reinforce or
make more powerful that basic neural revision. You're familiar
with --

DR. MCGAUGH: Sure.

DR. HURLBUT: Do you think this is something
that is coming? Is it realistic? Would it be profoundly disruptive?

And what do you see as the ethical questions
associated with that?

DR. MCGAUGH: Well, I hope it's not coming
because I think that the ramifications are really very broad.

The reason I hope it's not coming is
because you picked a particular case, but I could pick many others.
Let's just say the school teacher who is teaching the number facts
to the children, and number facts are not very exciting, but you need
to know how to multiply at least 12 times 12 and how to do the
division, and that's not any different than dealing with
dyslexics. You're trying to correct here a disorder.

The disorder is that they don't know the
number facts, and they have to know them or that they have to know the
grammar. And so why not a little chemical aid to do that?

So if you start with something as narrow as
that and say: folks, this is a very special case. We're going to
do this for the dyslexics under this condition because we think we can
give a drug to enhance this particular thing. All right? Then
we'll expand it. What about English literature? You know, how
about the sonnet? You know, memorization of the sonnet is due
tomorrow, or how about language? I have to learn German, as I did in
graduate school in four months in order to pass the exam. Wouldn't
that have been nice?

Well, we did have amphetamine in those days.
So that was helpful. Amphetamine and caffeine, as you know, were not
-- amphetamine was not controlled when I was a graduate student, and it
was commonly taken. Would keep you awake, but probably helped a little
bit.

No, I think that you've given a very
special case, but it's easy to make an argument for a large number
of cases. I don't know how you would constrain it after that. I
mean, that just happens to be his interest in what he's doing, but
other people are interested in other things, and they say, "Fine.
What we need is a little pharmacological help."

And now remember the basic thing I said is that
whether it's hormones, our own pharmacological agents or the ones
that we manipulate, we have never been able to do anything that we
can't do by just more training, never.

Now, in the case of Alzheimer's patient,
that isn't the case. With some subjects, particularly with Exelon,
which appears to be a little bit better than some of the others, they
can get them to do some things that they couldn't otherwise do. So
there's some help for a degenerating brain to make it work a little
better so that it can finally do something that it couldn't do.
That data on that are weak, but that's another case.

So I guess what I was trying to do is present
things here, which were tailor made for this group, and so in this
context I would say this is not immune from my criticism. It falls
into, let's say, my concern. It falls into my bag of concerns
because it is a very short step from there to giving the drug to my
neighbor to give her child because she's not going to tall the
child to work harder, but it's just a little bit easier to do.

It's sort of like taking a valium when
you're anxious rather than to use the anxiety to help cope with the
problem.

DR. HURLBUT: I hear a strong preference, if
not prejudice, for the natural in what you're saying because one
could argue, well, so what if it enhances one thing even at the expense
of the other.

What I was trying to say is that I don't
think that that special case solves the problem for us. If that works,
then I don't see any reason not to do it for any learning
condition.

I do favor the natural circumstance. I think I
would go back and say how can you become a better teacher to use the
naturally occurring devices that children have rather than to use some
ancillary treatment, which we know we're probably going to have to
do for the deteriorating brain, but that kid has all of the machinery.
The machinery is there. How can you make that machinery work better
would be the first approach that I think should be taken.

DR. HURLBUT: Well, you've convinced me
that I should be scaring my students more. A little more adrenalin
would help them learn better, but really --

DR. MCGAUGH: Let me -- let me -- I don't
think you're entirely wrong in the statement that you just made.
It's nice to be nice to people, but I just had to write something
about my earlier experiences recently, and the two teachers that I
singled out as having the biggest impact on my life were two of the
sternest teachers that I had.

I mean it just didn't dawn on me that until
I've thought about it pretty systematically. These were not
touchy-feely people. These were the most demanding teachers I ever had
in my life. One of them was my band and orchestra instructor whose aim
was to embarrass you in front of everybody else.

And so we knew that at any moment during
rehearsal he would stop it and point at somebody and say, "Play
the next 16 bars. Stand up and play the next 16 bars." At any
moment. Now, that kept our attention. It really did.

So if you want to get learning to take place
and have an impact, I don't think that roughness is necessarily
bad. I mean, it's better if they could do it in a nice way and
say, "Gee, Jim, would you do the next 16 bars? We'd sure love
to hear you do it in a nice way for the group."

You know, that would be helpful, but that's
not the way it was.

CHAIRMAN KASS: Rebecca and then we'll
take a break.

PROF. DRESSER: This is in line with some of
the other comments. I think at one point you said there is no memory
enhancing free lunch or something like that. I mean, the tone of your
presentation seems to me to be a good corrective to the media, kind of
public image about a lot of these prospects, which is there are always
going to be costs, financial costs, adverse effect costs, as well as
your great problem of what if we could arrest neurodegeneration in the
early stages of Alzheimer's disease. Would that be a good thing or
not?

I mean that's a very complicated question
socially. So thank you for the really, I think, balanced point of view
and perspective.

DR. MCGAUGH: Well, let me comment on that. I
do memory enhancement as a living, and that's what I do for a
living. So that's what my research is all about. So I
wouldn't want you to let me get out of here saying that I have
dissed memory enhancement.

But I think there is a role for it, and I think
it has been excessively over-hyped by pharmaceutical companies, biotech
companies, and by the press because it requires the kind of thoughtful
thinking that you people as a group have as your mission in order to
evaluate these things and find out what is the proper place.

I think that there may well be -- just as I
believe some children need Ritalin, all hyperactive children do not
need Ritalin. All right? I think there may be some children who need
memory enhancing drugs because they can't do it. They don't
have the machinery to do it in the same way that the deeply disturbed
hyperactive child does not have the machinery which enables normal
behavior.

So some children's brains will need this,
but once again, I come back to the slippery slope. Which ones do and
which ones don't and under what conditions and so on? And
that's a tough one. That's a tough one.

CHAIRMAN KASS: Let's take a break. the
conversation will continue. Let's take 15 minutes.

(Whereupon, the foregoing matter went off the
record at 3:24 p.m. and went back on the record at 3:44 p.m.)